Maternal RND3/RhoE deficiency impairs placental mitochondrial function in preeclampsia by modulating the PPARγ-UCP2 cascade

Preeclampsia (PE) is a life-threatening disease of pregnant women associated with severe hypertension, proteinuria, or multi-organ injuries. Mitochondrial-mediated placental oxidative stress plays a key role in the pathogenesis of PE. However, the underlying mechanism remains to be revealed. Here, we identify Rnd3, a small Rho GTPase, regulating placental mitochondrial reactive oxygen species (ROS). We showed that Rnd3 is down-regulated in primary trophoblasts isolated from PE patients. Loss of Rnd3 in trophoblasts resulted in excessive ROS generation, cell apoptosis, mitochondrial injury, and proton leakage from the respiratory chain. Moreover, Rnd3 overexpression partially rescues the mitochondrial defects and oxidative stress in human PE primary trophoblasts. Rnd3 physically interacts with the peroxisome proliferators-activated receptor gamma (PPAR gamma) and promotes the PPAR gamma-mitochondrial uncoupling protein 2 (UCP2) cascade. Forced expression of PPAR gamma rescues deficiency of Rnd3-mediated mitochondrial dysfunction. We conclude that Rnd3 acts as a novel protective factor in placental mitochondria through PPAR gamma-UCP2 signaling and highlight that downregulation of Rnd3 is a potential factor involved in PE pathogenesis.

Automated summary

Preeclampsia is a life-threatening disease in pregnant women associated with mitochondrial-mediated placental oxidative stress. The down-regulation of Rnd3 in primary trophoblasts from PE patients leads to excessive ROS generation, cell apoptosis, and mitochondrial damage. Rnd3 acts as a protective factor in placental mitochondria through the PPARγ-UCP2 signaling pathway.